Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1 or SHIP1) is a cytosolic protein that has been found to control the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and function as a negative regulator of cytokine and immune receptor signaling. Using various genetic models, it has been shown that SHIP1 deficient hosts are permissive for engraftment of major histocompatibility complex (MHC) mismatched bone marrow (BM) grafts, exhibit reduced GVHD post-transplant and delayed rejection of vascularized allogeneic heart grafts (Refs. 1-5). In addition, SHIP1 deficiency profoundly increases myeloid immunoregulatory (MIR) cell numbers and their function and granulocyte numbers (Refs. 2, 4, 6-8). These studies suggest that SHIP1 could be targeted to facilitate increase granulocyte/neutrophil numbers during infection or to reduce the severity and incidence of deleterious allogeneic T cell responses in bone marrow and organ transplantation (Ref. 5).
SHIP1, SHIP2 and PTEN are commonly viewed as opposing the activity of the PI3K/Akt signaling axis that promotes survival of cancer cells and tumors. However, the enzymatic activities of these inositol phosphatases are quite distinct in that the 3′-polyphosphatase activity of PTEN reverses the PI3K reaction to generate PI(4,5)P2 from PI(3,4,5)P3, while the 5′-poly-phosphatase activity of SHIP1/2 converts PI(3,4,5)P3 to PI(3,4)P2. This distinction is potentially crucial as it might enable SHIP1/2 and PTEN to have distinctly different effects on Akt signaling. The PH domain of Akt binds with greater affinity to the SHIP1/2 product PI(3,4)P2 leading to more potent activation of Akt than the direct product of PI3K, PI(3,4,5)P3 (Ref 9). Thus, SHIP1, which is expressed in most blood cell malignancies, might actually contribute to their growth and survival. Consistent with this hypothesis, PI(3,4)P2 levels are increased in leukemia cells (Ref. 10) and increased levels of PI(3,4)P2 promote the transformation and tumorigenicity of mouse embryonic fibroblasts (MEF) (Ref. 11).
To date the molecular structure of SHIP1 has not been determined and thus a rational design approach to develop SHIP1 inhibitors has not been feasible. Thus, High-Throughput Screening (HTS) tests have been used to identify compounds that can inhibit the enzymatic activity of SHIP1. However, there is a need for SHIP1 selective inhibitors that are capable of increasing granulocyte and MIR cell production in vivo and promoting apoptosis of blood cell cancers.
The present invention is directed to overcoming these and other deficiencies in the art.